ABSTRACT Inflammatory Bowel Disease (IBD) is a collective name for Crohn?s Disease and Ulcerative Colitis (UC). Both conditions manifest with a pathological inflammation of the bowel that causes breaks in mucosal integrity, frank ulceration and the risk of more severe complications. While the etiology of IBD is complex and not fully understood, the two distinguishing hallmarks of IBD are dysregulation of normal immune function and impaired epithelial repair. None of the currently available treatment modalities have a specific targeted effect to retain mucosal integrity or to heal breaches in the gut mucosa. Moreover, most drugs in development are focused on modifying the local inflammatory response and not on protection and repair of the intestinal epithelium. It is highly attractive if a treatment modality could indeed target the damaged gut mucosa, as this would complement approaches directed to the abnormal inflammatory response. Such a treatment paradigm would retain mucosal integrity and prevent or ameliorate a local breach, thereby reducing the impact infiltrating external (intra-luminal) factors may have on the pathophysiological process. Additionally, it could facilitate healing of breaches in the mucosa and restore integrity. Avexegen Therapeutics, Inc. in collaboration with Mark Frey?s group at Children?s Hospital, Los Angeles (CHLA), has identified Neuregulin-4 (NRG?4), a naturally occurring constituent of human breast milk, as a novel mucosal healing peptide. NRG-4 leverages physiological mechanisms to both directly protect the intestinal epithelium and to attenuate the inflammatory cascade. These actions have been shown to promote mucosal healing and the restoration of the damaged gut barrier in multiple experimental animal models of intestinal inflammation The NRG-4 product platform offers a wide range of product forms for the treatment of IBD. Based on the evidence gathered thus far, NRG-4 has a high potential for being a stand-alone treatment for these disorders or a complement to other treatment approaches. In this SBIR Phase I project, Avexegen aims to establish: (a) independent confirmation of pre-clinical findings from the Frey lab on the therapeutic potential of NRG-4 as a mucosal healing factor. This will be done by a 4 week in vitro potency determination study followed by an 8 week dose response study in a DSS mouse model. (b) Proof of concept of efficacy of oral administration in an IBD disease model. This will be done by first conducting a 4 week signaling study to demonstrate luminal ErbB4 receptor activation upon oral NRG-4 administration, and in vitro assessment of metabolic stability in a pancreatic digestive enzyme mix. Next, a 3 month analytical method and formulation development study will be conducted, and then followed with an 8 week dose-response study in a DSS mouse model using an oral NRG-4 formulation. These studies will add to the pre-clinical data package for filing the IND, and help transform IBD treatment and potentially other gastro- intestinal disorders where the repair and retention of intestinal mucosal integrity are key treatment objectives.